Article (Scientific journals)
Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor
Laulumaa, Saara; Hansen, Kathrine Voigt; Masternak, Magdalena et al.
2019In ACS Medicinal Chemistry Letters, 10 (3), p. 243-247
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Keywords :
Dimeric positive allosteric modulator; GluA2 ligand-binding domain; X-ray crystallography; Article; X ray crystallography
Abstract :
[en] The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator. © 2018 American Chemical Society.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Laulumaa, Saara;  Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, Copenhagen, DK-2100, Denmark
Hansen, Kathrine Voigt;  Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, Copenhagen, DK-2100, Denmark
Masternak, Magdalena;  Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, Copenhagen, DK-2100, Denmark
Drapier, Thomas;  Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), ULiège, Quartier Hôpital, Avenue Hippocrate, 15, B36, Liège, B-4000, Belgium
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Frydenvang, Karla;  Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, Copenhagen, DK-2100, Denmark
Kastrup, Jette Sandholm;  Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, Copenhagen, DK-2100, Denmark
Language :
English
Title :
Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor
Publication date :
2019
Journal title :
ACS Medicinal Chemistry Letters
eISSN :
1948-5875
Publisher :
American Chemical Society
Volume :
10
Issue :
3
Pages :
243-247
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
NIH - National Institutes of Natural Sciences
Available on ORBi :
since 20 May 2020

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